Hydrogenation of imine intermediates of sertraline with catalysts

ABSTRACT

Provided are hydrogenation processes of sertraline imine intermediates with catalysts in various reactors.

RELATED APPLICATIONS

This application is a continuation of application Ser. No. 10/825,386,filed on Apr. 14, 2004; which claims the benefit of U.S. ProvisionalPatent Application No. 60/462,816, filed Apr. 14, 2003, which isincorporated herein by reference.

FIELD OF INVENTION

The present invention relates to hydrogenation methods for preparationof sertraline.

BACKGROUND OF INVENTION

Sertraline hydrochloride, (1S-cis)-4-(3,4dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenaminehydrochloride, having the formula:

is approved, under the trademark Zoloft®, by the U.S. Food and DrugAdministration, as a serotonin re-uptake inhibitor for the treatment ofdepression, obsessive-compulsive disorder, panic disorder andpost-traumatic disorder. Only cis sertraline is therapeutically active.

U.S. Pat. No. 4,536,518 describes a synthesis of sertralinehydrochloride from sertralone having the following formula:

The process for synthesizing sertraline from sertralone has two steps.First, sertralone is condensed with methyl amine in the presence of anacid catalyst, to yield the Schiff base of sertralone,“sertraline-1-imine”:

The imine is then reduced to sertraline. The reduction process of U.S.Pat. No. 4,536,518 involves the hydrogenation of sertraline-1-imineconcentrate at room temperature for two hours over 10% Pd/C catalyst inan atmosphere of hydrogen (1 atm pressure). The product is a racemicmixture of the cis and trans diastereoisomers(“(±)-cis/trans-sertraline”) in the ratio of approximately 3 to 1. The'518 patent discloses that reduction with NaBH₄ gives a cis:trans ratioof about 1:1.

Two publications, WO 01/30742 and WO 98/27050, disclose thestereoselective reduction of sertraline-imine derivatives. Thepublication, WO 01/30742, discloses replacing the methyl group ofsertraline 1-imine with an optionally substituted bulky benzyl group toincrease the cis to trans ratio during hydrogenation, followed byadditional steps of converting the bulky group to a methyl group.Additionally, the publication, WO 01/30742, discloses: “The reductionmay be performed using complex hydrides (e.g. NaBH₄) or byhydrogenation. Reduction performed by catalytic hydrogenation tends togive better selectivity that reduction using the complex hydrides. Forexample, aliquots of N-[4-(3,4dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]-benzylamine werereduced with NaBH₄ and Raney nickel/H₂ respectively, and subsequentlyreductively alkylated with formaldehyde, whereafter the cis/trans ratiowas analyzed. The result was a ratio of 53.8/46.2 using NaBH₄ comparedto 82.9/17.1 for Raney nickel/H₂ which clearly demonstrates theselectivity for the catalytic hydrogenation. An even higher selectivitywith a cis/trans ratio of 93.5/6.5 has been observed using palladium oncarbon.”

The publication, WO 98/27050, discloses obtaining sertraline by reducingan N-oxide derivative of the imine. In Example 1, the N-oxide derivativeis hydrogenated with Raney nickel catalyst, while in Example 2 a 10%palladium on carbon is used as a catalyst. A cis product with an 81%yield is obtained in both instances. According to WO 98/27050, theN-oxide group may then be removed by addition of HCl to the N-oxidecompound in ethanol.

The publication, WO 01/16089, discloses a process of reductive aminationof sertralone to cis and trans sertraline. In Example 1, sertralone isreduced in the presence of Raney nickel and methylamine. The yieldprovided in Example 1 is 48-51% of the cis isomer.

The publication, WO 99/57093, discloses a process of selectivehydrogenation with a palladium catalyst pretreated with an alkyl halide.The publication discloses that the process of the '518 patent may leadto 10% of dechlorinated side products, while the process of thepublication has a “total amount of said contaminated by-products . . .below 0.5%.” In regards to the cis/trans ratio, the ratio provided is85-95% in the description of the invention. Alkyl halides however areproblematic for use on an industrial scale since halogenated reagentsare often not environmentally friendly.

U.S. Pat. No. 6,593,496 discloses preparing sertraline-1 imine byreacting sertralone with monomethylamine and either titaniumtetrachloride or molecular sieves. The hydrogenation illustrated inscheme 1 is carried out with a palladium catalyst in THF.

In US 2003/0105364, a process is provided for obtaining optically puresertralone through chromatography. The examples do not illustratehydrogenation.

In US 2003/0166970, a process for making (±)-sertraline with a cis/transratio of greater than about 3:1 is provided by hydrogenation ofsertraline-1-imine at a temperature of at least about 40° C. using apalladium or a platinum catalyst.

There is a need in the art for additional processes for hydrogenation ofimines for preparation of sertraline.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a process for preparingsertraline comprising the step of hydrogenating an imine of the formula:

with a cobalt catalyst and converting the hydrogenated compound tosertraline if necessary, wherein Y is optionally an oxygen atom.

In another aspect, the present invention provides a process forpreparing sertraline from an imine having the formula:

wherein Y is optionally an oxygen atom, comprising the step ofhydrogenating the imine with a metal catalyst in a trickel bed reactorand converting the hydrogenated compound to sertraline if necessary.

In another aspect, the present invention provides a process forpreparing sertraline from an imine having the formula:

wherein Y is optionally substituted with an oxygen atom, comprising thestep of hydrogenating the imine with a nickel containing catalyst havingfixed support in a batch reactor and converting the hydrogenatedcompound to sertraline if necessary.

In another aspect, the present invention provides a process forpreparing sertraline from sertraline-1-imine comprising the step ofreducing sertraline-1-iminine in a batch reactor with a Ni/SiO₂catalyst.

In another aspect, the present invention provides a process forpreparing sertraline from sertraline-1-imine comprising the step ofhydrogenating sertraline-1-imine in the presence of a catalyst in atrickel bed reactor.

In another aspect, the present invention provides a process forpreparing sertraline by providing a cobalt containing catalyst made upof cobalt fixed on an alumina-silica support, loading the catalyst in atrickel bed reactor, reducing the cobalt catalyst to an oxidation stateof CoO, feeding the reactor with hydrogen and a solution of sertraline1-imine in THF, recovering the sertraline and optionally converting thesertraline to sertraline hydrochloride.

In another aspect, the present invention provides a process forpreparing sertraline comprising hydrogenating sertraline-1-imine with acobalt catalyst in a trickle-bed reactor fed with sertraline iminesolution in THF of 30 g imine/L at weight hourly space velocity of about12.5 h⁻¹, a pressure of about 8 bar and a temperature of about 120° C.

In another aspect, the present invention provides a process forpreparing sertraline comprising hydrogenating sertraline-1-imine insolution in THF having a concentration in the range of about 10 to about140 g/L with a nickel catalyst fixed on a support in a trickle-bedreactor, at a temperature of about 65 to about 150° C., a pressure ofabout 2 to about 15 bar, a WHSV of about 40 to about 120 per hour, and ahydrogen feeding range of about 50 to about 2000 per hour.

In another aspect, the present invention provides a process forpreparing sertraline comprising hydrogenating with a nickel catalystfixed on a support in a batch reactor sertraline-1-imine in solution inTHF having a concentration in the range of about 30 to about 125 g/L,pressure of about 5 to about 8 bar, temperature range of about 65 toabout 150° C.

In another aspect, the present invention provides sertraline or ahydrochloride salt thereof in solid state comprising less than about0.1% of the dechlorinated side products as area percentage HPLCaccording to U.S. Pharmacopoeia, and their pharmaceutical compositions.In another aspect, the present invention provides a process forpreparing a cobalt catalyst suitable for reduction of sertraline-1-imineby calcining an alumina-silica support, evaporating moisture from thecalcined support, contacting the calcined support with an aqueoussolution of cobalt nitrate to saturate the surface of the support toobtain a catalyst, drying the catalyst and calcining the catalyst in thepresence of hydrogen to obtain an oxidation state of CoO.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term dechlorinated side (DCS) compounds refers tosertraline which is missing at least one of the chlorines on the phenylgroup. DCS-1 refers to the chlorine in the para position missing, andDCS-2, the chlorine in the meta position. DCS-3 refers to the impuritywithout any chlorine atom; its level is usually undetected unless thereaction is not carefully controlled. If the level of DCS-1 is more than1%, DCS-3 is also detected.

As used herein, the term calcine refers to heating to a high temperaturebut below the melting point, causing at least one of loss of moisture,reduction or oxidation, and decomposition of various compounds. Asuitable temperature is above about 450° C., most preferably about 500EC. Calcination of cobalt nitrate proceeds as following:Co(NO₃)₂ x6H₂O═CoO+2NO₂+0.5O₂+H₂O

Space velocity is calculated as follows: the mass/volume of feed perunit of catalyst per unit of time (e.g. WHSV=weight hourly spacevelocity=x kg-feed/kg-catalyst/hour). GHSV, gas hourly space velocity iscalculated as =v nL H₂ feed/L catalyst/hour.

The present invention provides for hydrogenation of an imine with anickel or a cobalt containing catalyst to obtain sertraline. Thefollowing catalysts may be used: Catalyst Type Promoters Ni, G-69(Sud-Chemie) Ni/Kieselguhr Zr Ni, (G-49 (Sud-Chemie) Ni/Kieselguhr — Pd((Johnson Matthey) Pd/C — (Trickel-bed reactor) Pd ((Johnson Matthey)Pd/Al₂0₃ — (Trickel-bed reactor) Co, T-4424 (Sud-Chemie) Co/proprietarysupport Mn, Mg Co, T-44o5(Sud-Chemie) Co/SiO₂-Al₂0₃ — Co, G-62(Sud-Chemie) Co/Si0₂-Al₂0₃ Ca TSCo-1 (BGU) 28% Co/_(y)-Al₂0₃ —TSCo-3(BGU) 23% Co/Si0₂ — TSCo-4(BGU) 25% Co/SA 3135 — TSCo-5 (BGU) 15%Co/SA 3135 — TSCo-6 (BGU) 15% Co/SA 3132

Pd/C was also used in trickle bed reactor, but the selectivity to cissertraline was not as good as that with cobalt (Table A). TABLE APerformance of Pd catalysts in trickle-bed reactor Feed Imine Cis- TotalTemp rate Conv, sertraline Sertralone DCS, Catalyst ° C. g/h % % % %0.8% Pd/C 40 25 90 60 2 2 5% Pd/Al₂O₃ 40 80 70 63 0.6 1

The imine used to obtain sertraline preferably has the followingstructure:

wherein in the most preferred embodiment Y is not substituted, i.e.,sertraline-1-imine. In another embodiment, Y is an oxygen atom, thusproviding the N-oxide compound disclosed in the publication WO 98/27050.Sertraline-1-imine is used as a starting material in the illustrationsof the present invention. The starting material may be racemic or a pureenantiomer of sertraline-1-imine, i.e. at least about 90% pure, morepreferably 95% pure. Such purity may be determined for example by achiral HPLC column, or rotation of light.

In one embodiment, an imine is hydrogenated with a commercial nickelcatalyst in a trickle-bed reactor. The nickel catalyst used may forexample be G-69, G-49 or G-96, supplied by Sud-Chemie (Munich, Germany).

The nickel catalyst preferably has a surface area of about 50 to about200, with about 150 m²/g being more preferred. The density of the nickelcatalyst is preferably from about 0.8 to about 1.5, with about 1.1 Kg/Lbeing more preferred. The granule size of the catalyst is preferablyabout 0.7 to about 5, with about 1 mm being more preferred. The amountof nickel deposited on the support is preferably about 30 to about 80,with about 45 (wt/wt) being more preferred.

With a trickle-bed, or another kind of a fixed bed reactor, theconditions used are preferably as follows:

A temperature of from about 65 to about 150, with about 90° C. beingpreferred.

A pressure of from about 2 to about 20, with about 8-10 bar beingpreferred.

An imine solution in THF having a concentration in the range of fromabout 10 to about 140, with about 30 g/L being preferred. Other solventsinclude methanol, ethanol, 1,4 dioxane, toluene and ethyl acetate.

A WHSV of from about 40 to about 120, with about 85 per hour beingpreferred.

A hydrogen feeding range of about 50 to about 2000 per hour.

In a preferred embodiment, the commercial catalyst G-69, supplied bySud-Chemie (Munich, Germany), is used under the following preferredconditions:

-   -   a trickle-bed reactor fed with sertraline-imine in        tetrahydrofuran (“THF”) at WHSV 77 h⁻¹;    -   pressure of from about 8 to about 10 bar;    -   temperature of about 90° C.; and    -   granules of the catalyst of from about 30 to about 50 mesh and        of about 50 to about 80 mesh.

The selectivity of cis and trans for this embodiment is preferably about86% and about 12% respectively. The cis/trans ratio is preferably about7.2:1, DCS-compounds content is preferably about 0.1% and the conversionis preferably complete.

In another embodiment, hydrogenation with a nickel containing catalyston fixed support is carried out in a batch type reactor with a nickelcatalyst. The following preferred reaction conditions may be used forthe hydrogenation process:

-   -   The reaction solvent: methanol, ethanol, toluene, ethylacetate,        1,4-dioxane and THF, with 1,4-dioxane and THF being more        preferred;    -   A reaction pressure of from about 5 to about 8 bar, with about 8        bar being preferred;    -   A temperature range of from about 65 to about 150° C., with from        about 120 to about 150° C. being more preferred; and    -   An imine loading range of from about 30 to about 125 g/L, more        preferably compared to THF.

The summary of the various runs with a batch type reactor is disclosedin Tables 1-4. Table 1 illustrates the high conversion rate obtainedfrom the G-69 catalyst, which is an Ni/Kieselguhr catalyst used with aZr promoter. Table 2 illustrates the high conversion rate and lowamounts of DCS obtained with THF as a solvent. Table 3 illustrates anincrease in yield with increase in temperature. Table 4 illustrates anincrease in yield with increase in pressure. TABLE 1 Hydrogenation withNi containing catalysts with a batch reactor: Catalyst DCS- Sertralone TP Loading, Cis- Compounds (% area Catalyst (C.) (bar) g/l Solvent SRT (%area HPLC) HPLC) Conversion G-69 65 5 4.7 MeOH 79.8 1.1 2 100 G-49 100 54.7 MeOH 68 0.1 2.5 69 G-96 65 5 4.7 MeOH 11 0.3 14.1 29.5 Ni-5249 70 53.1 MeOH 78.7 0.9 3 70

TABLE 2 Hydrogenation with catalyst G-69 in various solvents with abatch reactor: Cis- DCS- Sertralone Press., Temp., Conversion Sertralinecompounds (% area Solvent bar ° C. (%) (%) (% area HPLC) HPLC) MeOH 5 85100 79.9 1.2 2 EtOH 5 85 100 74.6 2.8 1 Toluene 5 120 93 69.1 0.1 6.9EtOAc 5 120 70 78.7 0.9 3 1,4-dioxane 5 120 93.7 81.6 0.04 6.2 THF 8 12099 83.4 0.02 1.4The catalyst loading was 4.7 g/l

TABLE 3 The results of the hydrogenation in THF with catalyst G-69 in abatch reactor: DCS- Sertralone Temperature Press., Cis-SertralineCompounds (% area (° C.) bar (%) (% area HPLC) HPLC) 65 5 79.2 0.08 3 955 81.1 0.21 2.1 120 8 82.3 0.24 1.5 150 9 83.7 0.3 2.1

TABLE 4 The effect of the pressure to the reaction with catalyst G-69 inTHF in a batch reactor: Cis- DCS- Sertralone Temp. Press., ConversionSertraline Compounds (% area (° C.) bar (%) (%) (% area HPLC) HPLC) 90 398.8 77.6 0.17 3 90 8 99 80.3 0.05 1.4

In another embodiment, a commercially available cobalt containingcatalyst or one as prepared in Examples 1-4 (“proprietary”) is used. Thecobalt commercial catalyst (G-62 supplied by Sud-Chemie) affords acis:trans ratio of about 11.8:1, and an amount of DCS-compounds of about<0.1%.

The cobalt catalyst may be prepared as illustrated in Examples 1-4.Granules of alumina-silica support are impregnated by a solution ofcobalt. The cobalt becomes fixed on the support. The cobalt catalyst isthen activated by being reduced with hydrogen to obtain an oxidationstate of CoO.

For example, the proprietary cobalt catalyst may be prepared bycalcining an alumina-silica support, evaporating moisture from thecalcined support, contacting the calcined support with an aqueoussolution of cobalt nitrate to saturate the surface of granules of thesupport to obtain a catalyst, drying the catalyst and calcining thecatalyst in the presence of hydrogen to obtain an oxidation state ofCoO. Preferably, calcining is carried out by heating to a temperature ofat least about 450° C., more preferably to a temperature of about 500°C. Preferably, the evaporating is carried out under reduced pressure,more preferably at less than about 100 mmHg, and most preferably lessthan about 50 mm-Hg. The drying is preferably carried out of about 90°C. to about 150° C., more preferably at a temperature is about 120° C.

The GHSV for the catalyst reduction is preferably from about 2000 toabout 2500 per hour, more preferably about 2500 h⁻¹. Preferably, thetemperature during reducing is increased (preferably from about roomtemperature) to at least about 450° C., more preferably to about 500°C., at interval of about 3-8° C./min, more preferably about 5° C./min,and maintained constant for at least about 2 hours, more preferably ofabout 2 hours to about 10 hours, and most preferably for about 4 hours.

The cobalt catalyst may be reactivated by removal of tar deposited onthe catalyst surface. After tar removal, the catalyst may be reducedagain if its oxidation state has substantially increased.

The proprietary cobalt catalyst (TSCo-3, TSCo-4 and TSCo-5) allowsreaching a cis:trans ratio of about 5.7:1 to 13.8:1, about <0.1%DCS-compounds, and at an imine conversion rate of from about 80 to about100%. The performance of the proprietary cobalt catalyst may beinfluenced by use of an optimal support, preferably alumina-silica,optimal content of cobalt oxide deposited on the support, and methods ofcatalyst preparation and activation as disclosed in Examples 1-4.

The cobalt catalyst preferably has a surface area of from about 6 toabout 100, with about 10 m²/g being more preferred. The pore diameterrange of the cobalt catalyst is preferably from about 100 to about 300,with about 180 angstroms being more preferred. The bulk density of thecobalt catalyst is preferably from about 0.7 to about 1.2, with about0.8 being preferred. The granule size of the catalyst is preferably fromabout 0.1 to about 3.5, with about 1 mm being preferred. The amount ofcobalt deposited on the support is preferably from about 10 to about 25,with about 15 (wt/wt) being preferred.

The cobalt catalyst packed in a column is then fed hydrogen and an iminesolution. Preferably the solvent used for the imine solution is THF.Other preferred solvents include methanol and 1,4 dioxane. Theconcentration of the imine solution is preferably from about 10 to about120, with about 30 gram/L being more preferred. The weight hourly spacevelocity is preferably from about 5 to about 15, with about 10 per hourbeing more preferred. Hydrogen is preferably fed at a rate of from about25 to about 5000, with about 3300 per hour being more preferred. Thetemperature is preferably from about 80 to about 150, with about 130 ECbeing more preferred. The pressure is preferably from about 5 to about20, with about 8 bar being more preferred.

The proprietary cobalt catalyst works optimally under the followingpreferred conditions: a trickle-bed reactor fed with sertraline iminesolution in THF (30 g imine/L) at weight hourly space velocity (“WHSV”)about 12.5 h⁻¹, pressure of about 8 bar and a temperature of about 120°C.

After hydrogenation, separation of the desirable cis isomer from theundesirable cis and anti isomer if needed may be carried out byselective precipitation with mandeleic acid, as disclosed in Example 5.(±)-cis/trans-Sertraline hydrochloride may also be recrystallized onceand dissolved in an appropriate organic solvent, such as ethanol,isopropanol, methanol, n-butanol, and iso-butanol. Ethanol is preferred.The optical resolution is performed by adding solid base, e.g.,potassium hydroxide, sodium hydroxide, sodium carbonate (Na₂CO₃) andsodium bicarbonate (NaHCO₃), directly to the sertraline hydrochlorideracemate solution. The salts are then removed by an appropriate method,e.g., by filtration. The optically active, selective precipitant, asdescribed above, e.g., (D)-mandelic acid, is added to the organicsolution and the (+)-cis-sertraline-precipitant, e.g.,(+)-cis-sertraline-mandelate, is precipitated directly from this organicsolution. The resulting crude (+)-cis-sertraline-precipitant isrecrystallized. The recrystallized (+)-cis-sertraline-precipitant, e.g.,(+)-cis-sertraline-mandelate, is dissolved in organic solvent and themandelic acid is removed with base, such as, by washing the organicsolution with aqueous basic solutions, e.g., 10-20% sodium hydroxide(NaOH) solution, or 10-20% potassium (KOH) solution. The(+)-cis-sertraline free base is isolated, dissolved in an appropriateorganic solvent, and is treated with hydrochloric acid.(+)-cis-Sertraline hydrochloride is precipitated as crystals and driedto give (+)-cis-sertraline hydrochloride Form V.

In addition to Form V, the sertraline may be crystallized as variouspolymorphic forms of sertraline hydrochloride as disclosed in U.S. Pat.Nos. 6,500,987, 6,495,721 and 6,452,054, incorporated herein byreference. In one embodiment sertraline hydrochloride Form II isprepared by bubbling HCl gas through a solution of sertraline inn-butanol.

Pharmaceutical compositions of the present invention contain sertralinehydrochloride containing less than about 0.1%, more preferably less thanabout 0.5%, of the dechlorinated side products as area percentage HPLCaccording to U.S. Pharmacopoeia. In addition to the activeingredient(s), the pharmaceutical compositions of the present inventionmay contain one or more excipients. Excipients are added to thecomposition for a variety of purposes.

Diluents increase the bulk of a solid pharmaceutical composition, andmay make a pharmaceutical dosage form containing the composition easierfor the patient and care giver to handle. Diluents for solidcompositions include, for example, microcrystalline cellulose (e.g.Avicel®), microfine cellulose, lactose, starch, pregelatinized starch,calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose,dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin,magnesium carbonate, magnesium oxide, maltodextrin, mannitol,polymethacrylates (e.g. Eudragit®), potassium chloride, powderedcellulose, sodium chloride, sorbitol and talc.

Solid pharmaceutical compositions that are compacted into a dosage form,such as a tablet, may include excipients whose functions include helpingto bind the active ingredient and other excipients together aftercompression. Binders for solid pharmaceutical compositions includeacacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulosesodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenatedvegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g.Klucel®, hydroxypropyl methyl cellulose (e.g. Methocel®), liquidglucose, magnesium aluminum silicate, maltodextrin, methylcellulose,polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinizedstarch, sodium alginate and starch.

The dissolution rate of a compacted solid pharmaceutical composition inthe patient's stomach may be increased by the addition of a disintegrantto the composition. Disintegrants include alginic acid,carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g.Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellosesodium, crospovidone (e.g. Kollidon®, Polyplasdone®), guar gum,magnesium aluminum silicate, methyl cellulose, microcrystallinecellulose, polacrilin potassium, powdered cellulose, pregelatinizedstarch, sodium alginate, sodium starch glycolate (e.g. Explotab®) andstarch.

Glidants may be added to improve the flowability of a non-compactedsolid composition and to improve the accuracy of dosing. Excipients thatmay function as glidants include colloidal silicon dioxide, magnesiumtrisilicate, powdered cellulose, starch, talc and tribasic calciumphosphate.

When a dosage form such as a tablet is made by the compaction of apowdered composition, the composition is subjected to pressure from apunch and dye. Some excipients and active ingredients have a tendency toadhere to the surfaces of the punch and dye, which may cause the productto have pitting and other surface irregularities. A lubricant may beadded to the composition to reduce adhesion and ease the release of theproduct from the dye. Lubricants include magnesium stearate, calciumstearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenatedcastor oil, hydrogenated vegetable oil, mineral oil, polyethyleneglycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate,stearic acid, talc and zinc stearate.

Flavoring agents and flavor enhancers make the dosage form morepalatable to the patient. Common flavoring agents and flavor enhancersfor pharmaceutical products that may be included in the composition ofthe present invention include maltol, vanillin, ethyl vanillin, menthol,citric acid, fumaric acid, ethyl maltol and tartaric acid.

Solid and liquid compositions may also be dyed using anypharmaceutically acceptable colorant to improve their appearance and/orfacilitate patient identification of the product and unit dosage level.

In liquid pharmaceutical compositions of the present invention,sertraline hydrochloride and any other solid excipients are dissolved orsuspended in a liquid carrier such as water, vegetable oil, alcohol,polyethylene glycol, propylene glycol or glycerin.

Liquid pharmaceutical compositions may contain emulsifying agents todisperse uniformly throughout the composition an active ingredient orother excipient that is not soluble in the liquid carrier. Emulsifyingagents that may be useful in liquid compositions of the presentinvention include, for example, gelatin, egg yolk, casein, cholesterol,acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer,cetostearyl alcohol and cetyl alcohol.

Liquid pharmaceutical compositions of the present invention may alsocontain a viscosity enhancing agent to improve the mouth-feel of theproduct and/or coat the lining of the gastrointestinal tract. Suchagents include acacia, alginic acid bentonite, carbomer,carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methylcellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin,polyvinyl alcohol, povidone, propylene carbonate, propylene glycolalginate, sodium alginate, sodium starch glycolate, starch tragacanthand xanthan gum.

Sweetening agents such as sorbitol, saccharin, sodium saccharin,sucrose, aspartame, fructose, mannitol and invert sugar may be added toimprove the taste.

Preservatives and chelating agents such as alcohol, sodium benzoate,butylated hydroxy toluene, butylated hydroxyanisole and ethylenediaminetetraacetic acid may be added at levels safe for ingestion to improvestorage stability.

According to the present invention, a liquid composition may alsocontain a buffer such as guconic acid, lactic acid, citric acid oracetic acid, sodium guconate, sodium lactate, sodium citrate or sodiumacetate.

Selection of excipients and the amounts used may be readily determinedby the formulation scientist based upon experience and consideration ofstandard procedures and reference works in the field.

The solid compositions of the present invention include powders,granulates, aggregates and compacted compositions. The dosages includedosages suitable for oral, buccal, rectal, parenteral (includingsubcutaneous, intramuscular, and intravenous), inhalant and ophthalmicadministration. Although the most suitable administration in any givencase will depend on the nature and severity of the condition beingtreated, the most preferred route of the present invention is oral. Thedosages may be conveniently presented in unit dosage form and preparedby any of the methods well-known in the pharmaceutical arts.

Dosage forms include solid dosage forms like tablets, powders, capsules,suppositories, sachets, troches and losenges, as well as liquid syrups,suspensions and elixirs.

The dosage form of the present invention may be a capsule containing thecomposition, preferably a powdered or granulated solid composition ofthe invention, within either a hard or soft shell. The shell may be madefrom gelatin and optionally contain a plasticizer such as glycerin andsorbitol, and an opacifying agent or colorant.

The active ingredient and excipients may be formulated into compositionsand dosage forms according to methods known in the art.

A composition for tableting or capsule filling may be prepared by wetgranulation. In wet granulation, some or all of the active ingredientsand excipients in powder form are blended and then further mixed in thepresence of a liquid, typically water, that causes the powders to clumpinto granules. The granulate is screened and/or milled, dried and thenscreened and/or milled to the desired particle size. The granulate maythen be tableted, or other excipients may be added prior to tableting,such as a glidant and/or a lubricant.

A tableting composition may be prepared conventionally by dry blending.For example, the blended composition of the actives and excipients maybe compacted into a slug or a sheet and then comminuted into compactedgranules. The compacted granules may subsequently be compressed into atablet.

As an alternative to dry granulation, a blended composition may becompressed directly into a compacted dosage form using directcompression techniques. Direct compression produces a more uniformtablet without granules. Excipients that are particularly well suitedfor direct compression tableting include microcrystalline cellulose,spray dried lactose, dicalcium phosphate dihydrate and colloidal silica.The proper use of these and other excipients in direct compressiontableting is known to those in the art with experience and skill inparticular formulation challenges of direct compression tableting.

A capsule filling of the present invention may comprise any of theaforementioned blends and granulates that were described with referenceto tableting, however, they are not subjected to a final tableting step.

Preferably, the pharmaceutical formulations of the present invention aresolid dosage forms in the form of a tablet for the oral administrationof sertraline hydrochloride. The highly pure sertraline hydrochlorideused for preparing a tablet may be in the form of fine crystals.Preferably, the fine crystals have a particle size distribution suchthat 100% of the particles are below 200 microns, more preferably below100 microns and most preferably below about 50 microns.

EXAMPLE 1 Preparation of the Proprietary Cobalt Catalyst

The catalyst was prepared using the incipient wetness impregnation ofalumina-silica. The support precursor catalyst reduction purchased fromSaint-Gobain N or Pro (Stow, Ohio) was first calcined at 500° C. for 12hours before impregnation. Characteristics of the support SA3 135 isgiven in Table 5. Calcined SA-3 135 (5 grams), granules 1-1.2 mm, wascharged into glass flask and evaporated at P=0.02 bar and 25° C. over 1hour. An aqueous solution of cobalt nitrate (4.0 ml) containing 4.36 gof Co(NO₃)₂x6H₂O (98%), purchased from Aldrich (Milwaukee, Wis.), wasadded dropwise so that surface of all the granules was saturated by thesalt solution. The catalyst was dried at 120° C. for 4 hours andcalcined at 500° C. for 4 hours.

The Energy Dispersive X-Ray (“EDX”) analysis indicated the contents ofCo, Al, Si, 0:15.0, 35.8, 13.8 and 35.4% wt., respectively. The XRDpatterns of the material were evident for the existence of the phaseCO₃O₄: (peaks at 2θ:18.96, 31.24, 36.68, 38, 78, 44.75, 57.55). Theaverage crystal size of CoO estimated in XRD study was 50 nm. Thecatalyst had surface area 11 m²/g, with an average pore diameter 183angstroms.

The catalyst (2.3 g) was loaded into a tubular stainless steal reactor(6 mm ID and 150 mm length). In the stream of hydrogen at GHSV (gas hourspace velocity) 2500 h⁻¹, the temperature was gradually ramped to 500°C., (5° C./min), and then the temperature was maintained constant at500° C. for 4 hours. The operating conditions of catalyst reduction wereselected over Temperature Programmed Reduction (“TPR”) studies carriedout in AMI-100 Catalyst Characterization System from Zeton-Altamira(Pittsburgh, Pa.).

The XRD analysis of the reduced catalysts indicates the existence of thephase Co and CoO (peaks at 2θ: 36.8, 42.47, 61.41, 73.69). After thecompletion of the catalyst reduction, the temperature in the reactor wasdecreased to 120° C., and the total pressure of hydrogen was increasedto 8 bar. A solution containingN-methyl-4(3,4-dichlorophenyl)-1-(-2H)-naphtalenimine (Imine) intetrahydrofuran (THF), purchased from BioLab (99.5%), having aconcentration of 30 g/L was then fed with hydrogen to the reactor. Therate of the solution feed was 25 g/h and the rate of hydrogen feed was150 ml/mm.

(The products were analyzed by GC HP6890 (Palo Alto, Calif.): capillarycolumn DB-17, 30 m×0.53 mm×1μ. The initial temperature was 160° C. for26 minutes, and then the temperature was increased at a rate of 30°C./min to 250° C.).

The results of the GC analysis under conditions mentioned above areshown in table 7, which indicates that the imine was completelyhydrogenated to a mixture containing:cis-(1S,4S)—N-Methyl-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphtalenamine(cis-Sertraline)as the major component,trans-(1S,4R)—N-Methyl-4(3,4-dichlorophenyl)-1,2,3,4-.tetrahydro-1-naphtalenamine(trans-Sertraline),(1S,4S)—N-Methyl-4(3-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphtalenamine(DCS-1),(1S,4S)—N-Methyl-4-(4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphtalenamine(DCS-2)and Sertralone.

The content of cis-sertraline in the product of imine hydrogenation was91%. TABLE 5 The characteristics of the support SA 3135 Parameter ValueAluminum oxide, % wt 79-81 Silicon oxide, % wt 17-19 Sodium oxide, % wt0.2-0.4 Ferric oxide, % wt 0.3-0.5 Titanium dioxide, % wt 0.4-0.5Magnesium oxide, % wt 0.1-0.3 Potassium oxide, % wt 0.1-0.3 Surfacearea, m²/g 12.5 Particle density, g/cc 1.1

EXAMPLE 2

A catalyst containing 11% cobalt by weight was prepared and reduced asin Example 1, but 3.2 g instead of 4.36 g of Co(NO₃)₂x6H₂O was used forthe preparation of the aqueous solution. The hydrogenation was carriedout under conditions as provided in Example 1. The content ofcis-sertraline in the product of imine hydrogenation was 91%.

EXAMPLE 3

The catalyst containing 25% of cobalt by weight was prepared by carryingout the incipient wetness impregnation process twice. The firstimpregnation was followed by drying at 120° C. for 4 hours, and thencalcination at 500° C. for 4 hours was carried out as in Example 1. SScanning Electronic Microscopy (“SEM”) analysis indicated that thecatalyst had 15% of Cobalt (5 g) impregnated for the second time by 4 mlof aqueous solution contained 2.2 g of Co(NO₃)₂x6H₂O. The catalyst wasdried and calcinated as mentioned above. The cobalt content aftertwofold impregnation was 25.1% (Scanning Electronic Microscopy (“SEM”)analysis). The catalyst (2.3 g) was charged in a tubular stainless stealreactor and reduced by hydrogen as in Example 1. The hydrogenation ofimine was carried out under operating conditions mentioned as inExample 1. The content of cis-Sertraline in the product was 87% (Table6).

EXAMPLE 4

Example 3 was repeated with the temperature of hydrogenation beingincreased to 150° C. and the feed rate of solution being increased to 40g/hr. The content of cis-sertraline was 88.8% (Table 6). TABLE 6 Theexperimental results of Imine hydrogenation in a trickel bed reactor GCanalysis, % area Exam- T Cis- Trans- DCS-1 + SRT- ples Catalyst (° C.)SRT SRT DCS-2 Imine one 1 15% Co 120 91.0 7.0 0.1 Not 0.3 SA-3135detected 2 11% Co 120 90.4 7.1 0.1 Not 0.2 SA-3135 detected 3 25% Co 12087.0 9.4 0.1 Not 0.7 SA-3135 detected  4* 25% Co 150 88.8 7.0 0.1 Not0.3 SA-3135 detectedThe content of imine in THF was 30 g/L, the feed of the solution was 25g/h and the feed of hydrogen was 150 ml/min (*the feed the Iminesolution was 40 g/h).

EXAMPLE 5 Resolution

(±)-Sertraline hydrochloride (5 g) was dissolved in ethanol (20 mL) andKOH powder (85%) was added to the solution. The slurry was stirred atroom temperature for 2.5 hrs. After stirring the solids were removed byfiltration and the solution was treated with D-(−)-mandelic acid (2.66g). Precipitation occurred and the stirring was continued for 24 hours.(+)-Sertraline-mandelate was isolated by filtration and washed withethanol and then dried to yield 2.70 g of (+)-sertraline-mandelate.

EXAMPLE 6

The catalyst G-69 (2.9 g) was loaded into a tubular stainless stealreactor (6 mm ID and 150 mm length). In the stream of hydrogen at GHSV(gas hour space velocity) 2500 h⁻¹, the temperature was gradually rampedto 150° C., (5° C./min), and then the temperature was maintainedconstant at 150° C. for 2 hours. After catalyst pre-treatment, thetemperature in the reactor was decreased to 90° C., and the totalpressure of hydrogen was increased to 8 atmospheres. A solutioncontaining N-methyl-4(3,4-dichlorophenyl)-1-(-2H)-naphtalenimine (Imine)in tetrahydrofuran (THF), purchased from BioLab (99.5%), having aconcentration of 30 g/L was then fed with hydrogen to the reactor. Therate of the solution feed was 250 g/h and the rate of hydrogen feed was150 ml/mm. The content of cis-sertraline in the product of iminehydrogenation was 86%.

Although certain presently preferred embodiments of the invention havebeen described herein, it will be apparent to those skilled in the artto which the invention pertains that variations and modifications of thedescribed embodiments may be made without departing from the spirit andscope of the invention. Accordingly, it is intended that the inventionbe limited only to the extent required by the appended embodiments andthe applicable rules of law.

1-22. (canceled)
 23. A process for preparing sertraline from an iminehaving the formula:

wherein Y is optionally an oxygen atom, comprising the step ofhydrogenating the imine with a metal catalyst in a trickel bed reactorand converting the hydrogenated compound to sertraline if necessary. 24.The process of claim 23, wherein the metal is nickel.
 25. The process ofclaim 24, wherein Y is not substituted.
 26. The process of claim 24,wherein the catalyst has an oxidation state of zero.
 27. The process ofclaim 24, wherein the catalyst has a nickel content of about 30 to about80% wt/wt.
 28. The process of claim 24, wherein the catalyst has asurface area of about 50 to about 200 m²/g.
 29. The process of claim 24,wherein the nickel is fixed to an alumina-silica support.
 30. Theprocess of claim 24, wherein the hydrogenating is carried out at atemperature of about 65 to about 150° C.
 31. The process of claim 30,wherein the temperature is about 90° C.
 32. The process of claim 24,wherein the hydrogenating is carried out at a pressure of about 2 toabout 15 bar.
 33. The process of claim 32, wherein the pressure is ofabout 8 to about 10 bar.
 34. The process of claim 24, wherein the imineis fed as a solution in THF having a concentration of about 10 to about140 grams/L.
 35. The process of claim 24, wherein the hydrogenating iscarried out with a weight hourly space velocity of about 40 to about 120per hour.
 36. The process of claim 24, wherein hydrogenating is carriedout with a hydrogen feed rate of about GHSV 50 to about 2000 per hour.37. The process of claim 24, wherein the catalyst has granules selectedfrom the group consisting of about 30 to about 50 mesh and about 50 toabout 80 mesh.
 38. The process of claim 24, wherein the sertraline has acis to trans ratio of about 7 to
 1. 39. The process of claim 24, whereinthe hydrogenating results in dechlorinated side products of about 0.1%.40. The process of claim 24, further comprising increasing ratio of(+)-cis-sertraline through selective precipitation with mandeleic acid.41. The process of claim 24, further comprising the step of convertingthe sertraline to sertraline hydrochloride. 42-62. (canceled)
 63. Aprocess for preparing sertraline from sertraline-1-imine comprising thestep of hydrogenating sertraline-1-imine in the presence of a catalystin a trickel bed reactor.
 64. The process of claim 63, wherein a cobaltcatalyst is used for hydrogenation. 65-75. (canceled)
 76. Sertraline ora hydrochloride salt thereof in solid state comprising less than about0.1% of the dechlorinated side products as area percentage HPLCaccording to U.S. Pharmacopoeia.
 77. The sertraline of claim 76, whereinthe dechlorinated compounds are about 0.05%.
 78. A pharmaceuticalcomposition comprising of sertraline hydrochloride of claim 76, and apharmaceutically acceptable excipient.
 79. A process for preparing acobalt catalyst suitable for reduction of sertraline-1-imine comprisingthe steps of: a) calcining an alumina-silica support; b) evaporatingmoisture from the calcined support; c) contacting the calcined supportwith an aqueous solution of cobalt nitrate to saturate the surface ofthe support to obtain a catalyst; d) drying the catalyst; and e)calcining the catalyst in the presence of hydrogen to obtain anoxidation state of CoO.
 80. The process of claim 79, wherein thecalcining is carried out by heating to a temperature of at least about450° C.
 81. The process of claim 80, wherein the temperature is about500° C.
 82. The process of claim 79, wherein evaporating is carried outunder reduced pressure.
 83. The process of claim 79, wherein the dryingis carried out of about 100° C. to about 140° C.
 84. The process ofclaim 83, wherein the temperature is about 120° C.
 85. The process ofclaim 79, wherein the hydrogen is added to a reactor at a rate of aboutGHSV 2000 h⁻¹ to about 3000 h⁻¹.
 86. The process of claim 85, whereinthe hydrogen is added at a rate of about GHSV 2500 per hour.
 87. Thecatalyst prepared by the process of claim 79.